The goal of this project is to learn more about the control of movement in normal humans and in patients with voluntary movement disorders such as Parkinson's disease, cerebellar ataxia, hemiplegia from stroke and dystonia. The tools we use include clinical neurophysiological methods such as electroencephalography, electromyography, and transcranial magnetic stimulation (TMS) and neuroimaging with positron emission tomography and functional magnetic resonance imaging (fMRI). Currently active projects in the Section include studies of normal physiology, the pathophysiology and treatment of dystonia, the bradykinesia in Parkinson?s disease, treatment of ataxia, and studies of recovery from hemiplegia. fMRI was used to investigate the underlying neural correlates of automatic movements. We trained normal subjects to perform sequential finger movements and found that compared to the pre-learning stage, movement automaticity was associated with less activation in bilateral premotor areas, parietal cortex, cerebellum, contralateral sensorimotor cortex and SMA. Pursuing the hypothesis that there are multimodal brain areas devoted to stimulus triggered movements, we showed such regions in right superior temporal cortex and right dorsal premotor cortex. Using functional MRI, neural substrates underlying motor imagination were explored in comparison with motor execution. The results indicate that motor imagination is associated with one of the functions of motor-related areas to process sensory information. Using functional MRI, we explored control mechanisms of upper facial movement and showed a major role of the rostral anterior cingulate cortex; this provides an alternative explanation for the common clinical observation of sparing of upper facial movement after stroke involving the middle cerebral artery. Another goal is to determine how parietal and frontal cortical regions participate during the preparation and execution of complex motor tasks. One observation using EEG is that the brain prepares for such movements much earlier than for simple movements. Pursuing the hypothesis that when there is a brain signal for a voluntary movement, other possible movements are actively inhibited, we showed with TMS that the brain representation of a muscle acting on the little finger was inhibited when the index finger was moved. We are doing studies with TMS to evaluate intracortical inhibition (ICI) in focal dystonia and in generalized dystonia of known genetic origin (DYT1 dystonia) in order to determine whether abnormalities of ICI may represent a marker of genetic predisposition for the development of dystonia. To test the presence of structural abnormalities in the brain of patients with focal hand dystonia compared with that of matched controls, we are using high resolution anatomical MRI and voxel-based morphometry to measure any group differences in the amount of gray matter. We have also evaluated modulation of inhibition within the motor cortex using TMS before and during movement in patients with focal dystonia. Motor evoked potentials were significantly suppressed in a ?surround? muscle in normal subjects, but enhanced significantly in patients with focal hand dystonia. These findings suggest disturbed surround inhibition in the motor cortex of patients with focal hand dystonia. Pursuing the hypothesis that motor training in patients with focal hand dystonia could decrease abnormal co-activation and improve dystonic symptoms, we supervised patients in a motor training program for four weeks. Dystonic symptoms improved using clinical evaluation scales. We conducted a review of clinical data on 1100 botulinum toxin injections in 140 focal hand dystonia patients and demonstrated that botulinum toxin injections are safe and effective treatment for focal hand dystonia over periods of time exceeding 10 years. We have completed a clinical study of mexiletine compared with placebo for the treatment of blepharospasm and focal hand dystonia. Results indicated that there was no statistically significant improvement in the group as a whole with mexiletine, however, there was a trend for benefit in blepharospasm. Using functional MRI and behavioral experiments, we are investigating the control mechanisms of how to move fast as well as how to think fast. This question is addressed with relation to pathophysiology underlying motor slowing (bradykinesia) and possible cognitive slowing (bradyphrenia) in patients with Parkinson's disease. An interim analysis suggests a partial overlap between the movement and cognitive control of speed, and definite bradykinesia with mild but significant bradyphrenia in Parkinson patients. We have completed an open trial of a gluten free diet in patients with ataxia and anti-gliadin antibodies, and showed that this treatment is promising for many patients. Following the observation, that there is an improvement of hand function in chronic stroke after local anesthesia of the upper part of the paretic arm, we are now trying to confirm these findings in a controlled study design.